Definisi

Epidemiologi

Klasifikasi

Etiologi & Faktor Risiko

Manifestasi Klinis

Diagnosis

Sistem staging

Terapi

An estimated 22,620 people diagnosed in the United

States in 2009; more common in other parts of the

world

Sixth most frequent cause of cancer-related death

among men and the ninth most common among

women

A disease in which normal liver cells grow

uncontrollably and form a tumor or tentacle-like

growth

Primary liver cancer is cancer that begins in the liver

Three types of primary liver cancer: hepatocellular

carcinoma (HCC), cholangiocarcinoma (bile duct

cancer), and angiosarcoma

HCC accounts for 90% of primary liver cancer cases

6th most common cancer world wide

• (626,000 or 5.7% of new cancer cases)

Third most common cause of cancer mortality

• Deaths = 598,000

Survival rates 3% - 5% for the US and

developing countries

Fastest growing cause of cancer-related death in

men in the US

• 19,160 cases and 16,780 deaths

Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55(2): p. 74-108.

Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.

Estimated Numbers of New Cancer

Cases and Deaths in 2002

• 6% 5 yr survival rate

#7

#6

Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.

Age-standardized Incidence Rates for Liver Cancer

In the US HCC rates are Asian>African Americans>Whites

Male>Female (2-4 fold)• Men are more likely to be infected with HBV and

HCV, consume EtOH, smoke, have increased iron stores

Peak age >65 in the US Incidence and death rates are increasing

in the US

El-Serag, H.B. and A.C. Mason, Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med, 1999. 340(10): p. 745-50.

JINAK GANAS

Tumor Epitelial

Adenoma hepatoselularAdenoma bilier intrahepatikSistadenoma bilier intrahepatikPapilomatosis bilier

Karsinoma hepatoselularKarsinoma fibrolamelarHepatoblastomaKolangiokarsinomaSistadenokarsinoma

Tumor Mesenkimal

HemangiomaFibromaLeiomiomaLipomaAngiomiolipomaLimfangiomaMesotelioma

AngiosarkomaFibrosarkomaLeiomiosarkomaLiposarkomaRabdomiosarkomaLimfoma hepatik primerHemangioendotelioma-epitelioid

Virus hepatitis B Virus hepatitis C Faktor-faktor risiko:

Sirosis hati, pada 60-80% SH makronodular dan 3-10% SH mikronodularAflatoksinObesitasDiabetes melitus hiperinsulinemia dan peningkatan insulin-like growth factors.AlkoholPenyakit hati autoimunPenyakit hati metabolik (hemokromatosis, defisiensi alfa-1-antitripsin, penyakit Wilson)Kontrasepsi oralSenyawa kimia (vinyl chloride, thorotrast, nitrosamin, insektisida organoklorin, asam tanik)Tembakau (masih kontroversi)

El-Serag, H.B. and K.L. Rudolph, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology, 2007. 132(7): p. 2557-76.

Brunetto M.R., O.F., Koehler M., et al., Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study.

International Interferon-alpha Hepatocellular Carcinoma Study Group. Lancet, 1998. 351(9115): p. 1535-9.

HBV

• 5-15 fold increased risk

• 70-90% of cases occur in setting of cirrhosis

• Treatment does NOT decrease risk

• Risk highest in carriers and lower in immune

HCV

• 1-3% of cirrhotic patients develop HCC

• Treatment seems to decrease risk Co-infection Aflatoxins (Aspergillus fumigatus)

• 4 fold increased risk HCC Alcohol

• >50-70g/day

• No link to direct carcinogenic effect

• Synergistic with HCV and HBV Nonalcoholic Steatohepatitis?

Obesity

Diabetes Mellitus

Hemochromatosis

Alpha-1 antitrypsin deficiency

Autoimmune hepatitis

Porphyrias

15-50% of HCC in the US have no

established risk factors

Gejala yang paling sering dikeluhkan:

Nyeri atau perasaan tak nyaman di kuadran kanan-atasabdomen, malaise, penurunan berat badan dan ikterus.Keluhan gastrointestinal lain adalah anoreksia, kembung, konstipasi atau diare.Sesak nafas sebagai akibat besarnya tumor yang menekan diafragma atau karena metastasis di paru.

Tanda-tanda klinis: Hepatomegali dengan atau tanpabruit hepatik, splenomegali, asites, ikterus, demam danatrofi otot.

Perdarahan varises esofagus, peritonitis bakterialisspontan.

Tanda-tanda sindroma neuropsikiatrik/mental confusion akibat kerusakan hebat sel-sel hati (ensefalopatihepaticum)

Alfa-fetoprotein: Protein serum normal yang disintesis oleh sel hati fetal, sel yolk-sac dansedikit sekali oleh saluran gastrointestinal fetal.

Nilai diagnostik atau sugestif untuk HCC bilakadar AFP > 400 ng/mL.

DCP (des-gamma carboxy prothrombin) atauPIVKA-2, pada HCC kadarnya akan meningkat.

AFP-L3 (suatu subfraksi AFP), memiliki angkasensitifitas dan spesifisitas paling baik untukHCC.

Ultrasonografi, memiliki sensitivitas 70-80%. Pada HCC yang kecil tampak gambaran

mosaik, formasi septum, bagian perifersonolusen (ber’halo’), bayangan lateral yang dibentuk oleh pseudokapsul fibrotik, sertapenyangatan eko posterior.

USG color Doppler sangat berguna untukmembedakan HCC dari tumor hepatik lain.

CT-scan, MRI serta angiografi kadang-kadangdiperlukan.

Laparoskopik biopsi Histopathology

“Hepatocellular carcinoma with cholangiolar features, moderately differentiated”

Numerous staging systems exist and NO CONSCENSUS• E.g. TNM, Okuda, CLIP, and BCLC

Incorporate 4 determinants of survival• Severity of underlying liver disease• Size of tumor• Extension of the tumor into adjacent structures• Presence of metastases

Primary staging should be clinical staging, and the CLIP is preferred

Secondary staging with the AJCC - TNM staging system for patients undergoing surgery

Staging work up includes Bone Scan and CT chest

Score Average survival

0 31 Mon.

1 27 Mon.

2 13 Mon.

3 8 Mon.

> 4 2 Mon.

Child – Pugh Stage Score

A 0

B 1

C 2

Tumor Morphology

Uninodular , <50% 0

Multinodular, <50% 1

Massive, >50% 2

AFP <400 0

>400 1

Portal Vein Thrombosis No 0

yes 1

A=5-6 (2 yr survival 85%)

B=7-9 (2 yr survival 57%)

C=10-15 (2 yr survival 35%)

Online Calculator: http://homepage.mac.com/sholland/contrivances/childpugh.htmlChild CG, Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension. Edited by CG Child. Philadelphia: Saunders 1964:50-64. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus in bleeding oesophageal varices. Br J Surg 1973;60:648-52

1 2 3

Bilirubin <2 2-3 >3

Albumin >3.5 3.5-2.8 <2.8

INR <1.7 1.7-2.3 >2.3

Ascites Absent Mild-Moderate Severe / Refractory

Encephalopathy Absent Mild (I-II) Severe (III-IV)

Berdasarkan Barcelona EASL ConferenceKriteria sito-histologisKriteria non-invasif (khusus untuk pasien sirosis hati):Kriteria radiologis: koinsidensi 2 cara imaging (USG/CT

scan/MRI/angiografi)- lesi fokal > 2 cm dengan hipervaskularisasi arterial

Kriteria kombinasi : satu cara imaging dengan kadar AFP serum:- lesi fokal > 2 cm dengan hipervaskularisasi arterial- kadar AFP serum ≥ 400 ng/mL

Dipakai sistem TNM (Tumor-Node-Metastases) yang dikelompokkan oleh American Joint Committee on Cancer (AJCC) sebagai berikut:

Primary tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Solitary tumor without vascular invasion T2: Solitary tumor with vascular invasion or multiple tumors none more than 5 cm T3: Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s) T4: Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum

Regional lymph nodes (N)NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis

Note: The regional lymph nodes are the hilar (i.e., those in the hepatoduodenal ligament, hepatic, and periportal nodes). Regional lymph nodes also include those along the inferior vena cava, hepatic artery, and portal vein.

Distant metastasis (M)MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis

[Note: Metastases occur most frequently in bones and lungs. Tumors may extend through the capsule to adjacent organs (adrenal glands, diaphragm, and colon) or may rupture, causing acute hemorrhage and peritoneal carcinomatosis.]

Stage I T1 N0 M0 55% 5 yr survival

Stage II T2 N0 M0 37% 5 yr survival

Stage IIIA T3 N0 M0 16% 5 yr survival

IIIB T4 N0 M0

IIIC Any T N1 M0

Stage IV Any T Any N M1

T definitions• T1 – solitary nodule without vascular invasion

• T2 – solitary tumor with vascular invasion or multiple nodules all <5cm

• T3 – multinodular >5cm, or tumor with major vasculature invasion

• T4 – Tumor with invasion of adjacent organsAJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc

Criteria Positive Negative

Tumor size >50% <50%

Ascites Clinically detectable Abscent

Albumin <3 >3

Bilirubin >3 <3

Adapted from Okuda, K, Ohtuiki, T, Obata, H, et al, Cancer 1985; 56:918.

Stage I No positive 8.3 mos survival

Stage II 1-2 positive 2 mos survival

Stage III 3-4 positive 0.7 mos survival

Localized resectable: cancer is in one place in the liver, can be removed through surgery and the other part of the liver is healthy

Localized unresectable: cancer is found in one part of the liver, but it cannot be removed by surgery

Advanced: cancer has spread throughout the liver and/or to other parts of the body, such as the lungs and bones

Recurrent: cancer has come back after treatment. It may recur in the liver or another part of the body

More than one treatment may be used

Surgery, including liver transplantation

Radiation therapy

Chemotherapy: systemic and regional

Targeted therapy

Ablative therapies, including

percutaneous ethanol injection and

radiofrequency ablation

Arterial chemoembolization

Clinical trials

Large tumor size, vascular invasion, poor functional status, and nodal metastases

DNA microarrays• Signatures can predict OS, recurrence and change

with advanced HCC

• Since 2000 over 30 articles have been published

Thorgeirsson. J Hepatology. 2006. 44:798Lee Hepatology. 2004. 40(3):667

Primary prevention• Taiwan: HBV immunization of newborns

introduced in 1984 resulting in decrease in

incidence of HCC

0.7 to 0.36 per 100,000 children

• Infant vaccination estimated to prevent 84% of

HBV related deaths

94% of deaths occur from cirrhosis and HCC

Chang, M.H., et al., Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.

Taiwan Childhood Hepatoma Study Group. N Engl J Med, 1997. 336(26): p. 1855-9.

Liver transplantation / Resection (<5% of

cases)• 5 yr survival 41-93%

Radiofrequency ablation (RFA) (20-30% of

cases)• 5 yr survival 33-40%

• Solitary tumors, max 3-5cm

Percutaneous ethanol or acetic acid ablation• 5 yr survival 29-71%

• Solitary tumors, max 3-5cm

Transarterial chemoembolization (TACE)• 2 yr survival 24-63%

• No vascular invasion, preserved liver function,

no extrahepatic spread

Radiation therapy

Systemic chemotherapy

>100 trials over the last 30 years

Transarterial chemoembolization (TACE)• 2 yr survival 24-63%

• No vascular invasion, preserved liver function,

no extrahepatic spread

Radiation therapy

Systemic chemotherapy

>100 trials over the last 30 years

Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917

Reseksi hepatik: untuk pasien dalam kelompok non-sirosis (klasifikasi Child Pugh A) dan fungsi hati normal.

Reseksi juga pada kelompok HCC lokalisata (kelainan pada satu lobus hati/(Selected T1 and T2; N0; M0) ), bagian hati yang direseksi termasuk bagian normal hati ±1cm.

Transplantasi hati: untuk pasien HCC dan sirosis hati. Pada pasien HCC lokalisata yang parah/advance

(Selected T1, T2, T3, and T4; N0; M0), bila tidak dilakukan reseksi Ablasi tumor perkutan: Injeksi etanol perkutan; Radiofrequency ablation; Polyprenoic acid.

Terapi paliatif: Transarterial embolization/chemo embolization khususnya pada HCC difus dua lobus atau belum ada metastase ekstrahepatik. Bila ada metastase ekstrahepatik, angka mortalitasnya tinggi. (Any T, N1 or M1)

HCC has been considered to be a relatively

chemotherapy refractory tumor

Survival is often determined by degree of

hepatic dysfunction

Systemic chemotherapy not well tolerated

by patients with significant underlying

hepatic dysfunction

Systemic chemotherapy is injected into a vein and travels

through the bloodstream to the whole body

Regional chemotherapy uses a small pump surgically placed in

the body to deliver anticancer drugs directly to the blood

vessels that feed the tumor

Hepatic arterial infusion is chemotherapy injected into a

catheter in the major artery supplying blood to the liver

Chemoembolization is similar to hepatic arterial infusion except

the flow of blood through the artery is blocked for a short time,

so the anticancer drug stays in the tumor longer; the blocking of

the blood supply to the tumor also kills the cancer cells

Targets faulty genes or proteins that contribute to

cancer growth and development

Sorafenib (Nexavar), an anti-angiogenic and anti-

proliferative drug (starves the tumor by disrupting

its blood supply), may be used to treat tumors that

cannot be removed with surgery

Approved in 2007 for treating patients with

advanced HCC